HOXC10上调通过丝裂原活化蛋白激酶（MAPK）途径促进胃癌细胞增殖和转移。
HOXC10 up-regulation promotes gastric cancer cell proliferation and metastasis through MAPK pathway.
作者信息
Guo Chen, Hou Jianing, Ao Sheng, Deng Xingming, Lyu Guoqing
机构信息
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China.
出版信息
Chin J Cancer Res. 2017 Dec;29(6):572-580. doi: 10.21147/j.issn.1000-9604.2017.06.12.
OBJECTIVE
As an important regulator of embryonic morphogenesis, homeodomain-containing gene 10 () has been found to promote progression of human cancers and its expression indicates poor survival outcome. However, very few studies are available on the role of HOXC10 in gastric carcinoma. Therefore, the aim of this study was to determine the role of HOXC10 in gastric cancer and the potential mechanism underlying its function for cancer biology.
METHODS
A primary gastric cancer mouse model was obtained via intra-gastric wall injection of gastric cancer cells and was used to evaluate the function of HOXC10 during gastric cancer progression . Immunohistochemistry was performed to visualize and measure HOXC10 protein expression in gastric cancer tissue. Cells were transfected with plasmids to increase the expression of , and siRNA transfection was performed to suppress expression. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were utilized to measure mRNA and protein expression, respectively. Proliferation, migration, and invasion were investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, wound healing assay, and matrigel invasion assay , respectively.
RESULTS
HOXC10 expression was significantly increased in gastric cancer tissues compared to matched normal tissues. HOXC10 up-regulation significantly increased tumor volumes in nude mice. Plasmid transfection significantly increased HOXC10 protein and mRNA expressions and effectively promoted cell proliferation. Moreover, HOXC10 up-regulation significantly promoted migration and invasion of gastric cancer cells. Mechanistic investigation showed that HOXC10 up-regulation significantly increased mRNA and protein expression of mitogen-activated protein kinase (MAPK) signaling related genes, including , and , while also modulating the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38 but not their total protein levels.
CONCLUSIONS
This study demonstrated the tight link between HOXC10 and gastric cancer cell proliferation and metastasis via involvement of the MAPK pathway.
目的
作为胚胎形态发生的重要调节因子，含同源结构域基因10（HOXC10）已被发现可促进人类癌症进展，其表达提示生存预后不良。然而，关于HOXC10在胃癌中的作用的研究非常少。因此，本研究的目的是确定HOXC10在胃癌中的作用及其影响癌症生物学功能的潜在机制。
方法
通过胃壁内注射胃癌细胞获得原发性胃癌小鼠模型，用于评估HOXC10在胃癌进展过程中的功能。采用免疫组织化学法观察并检测胃癌组织中HOXC10蛋白的表达。用质粒转染细胞以增加HOXC10的表达，并用小干扰RNA（siRNA）转染以抑制HOXC10表达。分别采用逆转录聚合酶链反应（RT-PCR）和蛋白质印迹法检测mRNA和蛋白质表达。分别用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法、伤口愈合试验和基质胶侵袭试验研究细胞增殖、迁移和侵袭情况。
结果
与配对的正常组织相比，胃癌组织中HOXC10表达显著增加。HOXC10上调显著增加裸鼠肿瘤体积。质粒转染显著增加HOXC10蛋白和mRNA表达，并有效促进细胞增殖。此外，HOXC10上调显著促进胃癌细胞的迁移和侵袭。机制研究表明，HOXC10上调显著增加丝裂原活化蛋白激酶（MAPK）信号相关基因（包括c-fos、c-jun和c-myc）的mRNA和蛋白质表达，同时还调节c-Jun氨基末端激酶（JNK）、细胞外信号调节激酶（ERK）和P38的磷酸化，但不影响其总蛋白水平。
结论
本研究证明HOXC10通过参与MAPK途径与胃癌细胞增殖和转移密切相关。
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